The objective of this Research Program-Project is to achieve greater comprehension of the pathogenesis of multiple sclerosis (MS). How important is genetic susceptibility? There is an inreased incidence of MS in families. In families with more than one person afflicted, we have evidence for an HLA-linked MS susceptibility gene with a penetrance of about 5%. We also have found elevated measles antibodies in many MS patients and their healthy siblings. Recently, we discovered 15% of apparently normal first degree relatives of MS patients have abnormal evoked potentials. We propose to seek associations among HLA type, measles and other antibody titers, abnormal evoked potentials, and clinical MS. The elevated measles antibodies in MS and family members could result from aberrant immune regulation. We will investigate the cellular basis for the regulation of immunoglobulins and specific antibodies in people with MS and appropriate controls. Certain subsets of the mononuclear cells performin immune functions carry surface markers whih allow separaton and detailed description of function. We recently discovered a subset (T gamma mu), which appears to be unique to MS. We propose to extend our studies of this subset to determine the origin and function of these cells. Immunologic mechanisms quite likely are involved in symptom formation and demyelination. We will explore this hypothesis by systematically manipulating the different components of the immune response with biologic response modifiers. We postulate there will be a correlation between changes in immune functions and change in clinical course. Finally, we shall determine the utility of evoked potentials as an adjunct for detection of changes in the clinical course of those receiving placebos or targeted biologic response modifiers.